Field of Invention
The disclosure is in the field of novel sulfonamide compounds, particularly for use as inhibitors of carbonic anhydrase IX and XII, in the treatment of hypoxic and metastatic cancer, and the depletion of cancer stem cells in mammals.
Description of Related Art
Sixteen different α-carbonic anhydrase (CA) isoforms have been isolated and characterized in mammals, where they play important physiological roles. Some of them are cytosolic (CAI, CAII, CAIII, CAVII, CAXIII), others are membrane-bound (CAIV, CAIX, CAXII, CAXIV and CAXV), CA VA and CA VB are mitochondrial, and CAVI is secreted in saliva and milk. The mammalian CAs were the first such enzymes isolated and studied in detail (Supuran, C T. Nat. Rev. Drug Discov. 2008, 7, p 168, Supuran, C. T.; Scozzafava, A. Bioorg. Med. Chem. 2007, 15, 4336) and many of them are established therapeutic targets. The classical CA inhibitors are the primary sulfonamides, RSO2NH2, which have been in clinical use for more than 50 years as diuretics and antiglaucoma drugs. In fact there are around 30 clinically used drugs (or agents in clinical development) belonging to the sulfonamide or sulfamate class which show CAs inhibitory activity (Supuran, C. (2008) Nature, Vol 7: 168-181) and some of which are established as diuretics and antiglaucoma agents.
It has recently emerged that CA inhibitors have potential as, inter alia, anticancer drugs. However critical barriers to the design of CA inhibitors as therapeutic agents are related to the high number of isoforms in humans (i.e., 16 CAs, of which 13 have catalytic activity), their rather diffuse localization in many tissues/organs, and the lack of isozyme selectivity of the presently available inhibitors of the sulfonamide/sulfamate class. In fact, among derivatives mentioned above, there are no compounds which selectively inhibit CA isoforms with therapeutic value (inhibition data of 1-25 sulfonamide compounds against all human (h) CA isoforms are provided in Supuran, C. (2008) Nature 7: 168-181.
Isozymes CAIX and CAXII are predominantly found in tumor cells and show a restricted expression in normal tissues. A helpful overview of the limitations of current CAI is provided in Poulsen, Expert Opin. Ther. Patents (2010) 20(6):795-806. It is clear from this review that the use of CAIX inhibitors for cancer and metastasis has not been demonstrated effectively, due to the limitations of the compounds available.
Evidence that certain sulfonamide CAIX inhibitors may indeed show antitumor effects, has been only very recently published (Ahlskog, J. K. J.; Dumelin, C. E.; Trüssel, S.; Marlind, J.; Neri, D. Bioorg. Med. Chem. Lett. 2009, 19, 4851.) Certain compounds have been disclosed, for example in Maresca et al., PCT publication WO2009089383. Selectivity is an issue, however, as inhibition of housekeeping carbonic anhydrases is contraindicated.